The overall goal of this project is to study the processes of B-cell growth and development, especially as regards the role of the B-cell receptor (BCR) complex. The principal experimental approach used will rely on transgenic mice and transfectants expressing signal-competent and -incompetent BCR complexes. This detailed mechanistic analysis of B-cell development is relevant to the understanding of leukemic transformation of B-cells as well as the defect in immunodeficiencies such as X-linked agammaglobulinemia. The project has 2 main goals: 1) The role of the BCR and BCR complex in the pre-B-cell developmental control mechanism. Transgenic mice have been generated that express normal and signal-incompetent BCR molecules. The pattern of B-cell development and the mechanisms of B-cell developmental defects will be analyzed in these mice. This analysis will then be extended using in vitro studies of pre-B signaling in transformed cell lines, utilizing transfection wild type and mutant BCR molecules into pre-B lines followed by analysis of the impact on delivering a differentiation and survival signal to the pre-B-cell, Ig heavy chain also directs the process of ordered gene rearrangement and allelic exclusion which ensures monospecificity of each B-cell. The underlying hypothesis is that signals which drive B-cell development and allelic exclusion are different and delivered by distinct signaling pathways. Allelic exclusion will be analyzed at the phenotypic as well as the genomic clonal populations. Specific signaling mechanisms will be studied using these lines and the transfected lines developed in Aim 1. The studies proposed here build on previous successful approaches in analyzing the role of the B-cell receptor complex in B-cell signaling, and seek to address issues of fundamental importance. Both the tools and the intellectual infrastructure now exist to study the earliest phases of B-cell development in the same manner that mature B-cell proliferation and differentiation have been studied.